Abstract Body (Do not enter title and authors here): Background: Chagas disease (CD), caused by Trypanosoma cruzi, leads to chronic Chagas cardiomyopathy, one of the deadliest and most debilitating cardiopathies. Benznidazole (BZN) is the medication of choice in Brazil, effective during the acute phase, but its efficacy during the chronic phase is unclear. Aims: To determine if BZN treatment reduces cardiac inflammation and fibrosis via magnetic resonance imaging (MRI) and its association with the circulating immune profile of CD patients. Methods: We collected cardiac images and plasma from a cohort of CD patients before and 6 months after BZN treatment. We performed: 1- MRI of left and right ventricle function and volumes, T1 (MAPA T1), T2 mapping (MAPA T2), and extracellular volume (ECV); 2- analysis of soluble factors including cytokines, chemokines, and growth factors using the Bio-48 Plex Human Cytokine Screening Panel kit. Changes in the variables MAPAT1, MAPAT2, and ECV were used to classify the improvement of CD patients undergoing BZN therapy. Patients with the greatest reductions in these variables post-therapy, compared to pre-therapy, were considered to have greater clinical improvement. Thus, patients were divided into two groups: greater clinical improvement (GCI; n=15) and smaller clinical improvement (SCI; n=15) (figure 1). Data were analyzed using GraphPad Prism 8 software with statistical significance set at p<0.05. Results: Analysis of MAPA T1, MAPA T2, and ECV showed a reduction of fibrosis/inflammation in patients after treatment as compared to before. Our data demonstrated that GCI patients had an activated systemic immune profile before treatment, with higher levels of NGF (p=0.04), CXCL-8 (p=0.03), CCL-7 (p=0.04), IL-12 (p=0.04), IL-13 (p=0.03), and IL-15 (p=0.03) compared to SCI patients (figure 2A). Interestingly, GCI patients displayed higher post-treatment levels of IL-16 (p=0.02) and IL-17 (p=0.048) (figure 2B). Conclusion: These results suggest that BZN treatment may reduce fibrosis/inflammation in cardiac tissue of CD patients and that an activated immune profile before therapy may predict therapeutic response. Additionally, increased levels of IL-17 post-therapy in GCI patients support IL-17's previously reported protective role in Chagas disease.